Corneal transplantation is the oldest, most common, and arguably, the most successful form of organ transplantation. In the United States alone, over 45,000 corneal transplants are performed annually. Less than 10% of first time, uncomplicated keratoplasties will fail. By contrast, the rejection of second corneal allografts or keratoplasties performed on vascularized graft beds rises to over 65%. The leading cause of corneal graft failure - whether it occurs in the low risk keratoconus patient or the high risk host who has rejected a previous corneal transplant - is immune rejection. Understanding the immune mechanisms of corneal graft rejection and developing strategies to prevent alloimmune responses are of paramount importance in preserving vision and preventing blindness in a very large population of patients. These two goals will be pursued by addressing three specific aims. The first aim will determine the immune mechanisms of corneal graft rejection that do not involve the participation of CD4+ T cells. The roles of interferon-gamma, tumor necrosis factor-alpha, and CD95-induced apoptosis will be explored prospectively. The second specific aim will ascertain the immune effector mechanisms that culminate in corneal graft rejection in "high-risk" hosts. Based on previous studies from our laboratory and others, we predict that the mechanisms invoked to reject corneal allografts in "high-risk" hosts are fundamentally different from those mediating rejection in normal, first-time hosts. The third specific aim will further characterize the clinical parameters of oral immunization as a strategy for reducing the risk of corneal graft rejection. Oral administration of alloantigenic cells from corneal allograft donors induces the down-regulation of immune responses to donor alloantigens and as a result, enhances allograft survival. This phenomenon is termed "oral tolerance" and holds promise for reducing the risk of corneal allograft rejection in the "high-risk" patients. All three of these aims will be addressed in a well-characterized mouse model of penetrating keratoplasty.